This application is the National Stage filed under 35 USC 371 of PCT/JP98/04896, filed Oct. 29, 1998.
The present invention relates to a piperazine-cyclodextrin complex which exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent for circulatory diseases and diseases of the brain region.
Piperazine derivatives represented by the below-described formula (I) have been known to exhibit calmodulin-inhibition and to be useful as therapeutic agents for circulatory diseases and diseases of the brain region (Japanese Patent Application Laid-Open (kokai) No. 7-97364).
However, due to their poor water solubility, the piperazine derivatives (I) are difficult to be incorporated into an injection formulation. Even though an injection formulation is prepared from the piperazine derivatives (I), when the content of the derivatives increases, the formulation tends to provide topical stimulation due to hemolysis activity and vascular permeability attributed to the piperazine derivatives. Furthermore, there has also been a problem that the formulation has relatively low stability against light and its active component thereof is adsorbed on the container, depending on the material of the container, to thereby reduce the efficacy.
Therefore, an object of the present invention is to provide a piperazine-cyclodextrin complex which exhibits enhanced water solubility, excellent stability, and low topical stimulation.
In the light of the foregoing, the present inventors have conducted earnest studies and have found that a piperazine-cyclodextrin complex formed of a piperazine derivative represented by the below-described formula (I) and a water-soluble cyclodextrin derivative exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent for circulatory diseases and diseases of the brain region. The present invention was accomplished based on this finding.
Accordingly, the present invention provides a piperazine-cyclodextrin complex formed of a piperazine derivative or a salt thereof and a water-soluble cyclodextrin derivative, wherein the piperazine derivative is represented by formula (I): 
wherein Q represents
(1) an aryl group,
(2) a heterocyclic group,
(3) a diarylmethyl group,
(4) an aralkyl group formed of an aryl group and a C1-C6 alkylene group,
(5) a C1-C8 alkyl group, or
(6) a C3-C8 cycloalkyl group,
wherein each of the aryl group, the heterocyclic group, and the aryl groups in the diarylmethyl group and the aralkyl group may have one or more substituents selected from among the following groups:
1) a C1-C6 alkyl group,
2) a C1-C6 alkoxyl group,
3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group,
4) a trifluoromethoxyl group and a 2,2,2-trifluoroethoxyl group,
5) a C1-C6 alkylthio group,
6) a C1-C6 alkylsulfinyl group,
7) a C1-C6 alkylsulfonyl group,
8) an alkanoyl group formed of a C1-C6 alkyl group and a carbonyl group,
9) a C2-C7 alkanoyloxy group,
10) a C2-C7 alkanoylamino group,
11) an amino group,
12) a monoalkylamino group having a C1-C6 alkyl group,
13) a dialkylamino group wherein each of the alkyl groups is a C1-C6 alkyl group,
14) a hydroxyl group,
15) a halogen atom,
16) a C2-C6 perfluoroalkyl group,
17) a cyano group,
18) a nitro group,
19) a carboxyl group,
20) an alkoxycarbonyl group formed of a C1-C6 alkoxyl group and a carbonyl group,
21) a tetrazolyl group,
22) a sulfamoyl group,
23) a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group,
24) a morpholinosulfonyl group,
25) a piperazinosulfonyl group,
26) a 4-alkylpiperazinosulfonyl group having a C1-C6 alkyl group,
27) a 4-(dialkylamino)piperidino group having a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other,
28) a 4-(monoalkylamino)piperidino group having a C1-C6 alkyl group, and
29) a 4-aminopiperidyl group;
R represents a bicyclic nitrogen-containing heterocyclic group (i) or a phenyl group (ii), wherein the nitrogen-containing heterocyclic group has a condensed ring structure formed of a 5-membered ring and a 6-membered ring; one or two nitrogen atoms are contained in the 5-membered ring portion; the nitrogen-containing ring may be an aromatic or saturated ring; and the saturated ring may contain a ketone moiety; wherein the 5-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) is substituted with substituent G selected from the group consisting of the following groups:
(aa) a C1-C6 alkyl group,
(ab) a phenyl group which may have a substituent,
(ac) a benzyl group which may have a substituent in the phenyl group portion,
(ad) a benzoyl group which may have a substituent in the phenyl group portion,
(ae) a benzylcarbonyl group which may have a substituent in the phenyl group portion,
(af) a benzoylmethyl group which may have a substituent in the phenyl group portion,
(ag) an xcex1-hydroxybenzyl group which may have a substituent in the phenyl group portion,
(ah) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
(ai) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as a heteroatom one nitrogen atom and as a second heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the second heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
(aj) a 5-membered aromatic heterocyclic group which may have a substituent and which contains as heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the nitrogen-containing heterocyclic group or for the phenyl group,
(ak) a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms,
(al) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which may have a substituent and contains as a heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group,
(am) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which may have a substituent and contains as a heteroatom one nitrogen atom and as a second heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the second heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the alkylene group,
(an) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 5-membered aromatic heterocyclic group, which 5-membered aromatic heterocyclic group may have a substituent and contains as heteroatoms two nitrogen atoms and as a third heteroatom a nitrogen atom, an oxygen atom, or a sulfur atom; wherein when the third heteroatom is a nitrogen atom, the nitrogen atom is bonded to a hydrogen atom or to a C1-C6 alkyl group, or the nitrogen atom serves as the bonding site for the alkylene group,
(ao) a heterocyclic group-substituted alkyl group formed of a C1-C3 alkylene group and a 6-membered aromatic heterocyclic group which may have a substituent and which contains one or two nitrogen atoms,
(ap) a phenylhydroxyalkyl group formed of a C2-C3 alkylene group having one hydroxyl group and a phenyl group which may have a substituent,
(aq) a 2-phenylethynyl group wherein its phenyl group may have a substituent,
(ar) a tetrazolyl group,
(as) a morpholino group,
(at) a C2-C7 alkanoylamino group,
(au) a tetrazolylalkyl group formed of a tetrazolyl group and a C1-C3 alkylene group wherein the alkylene group is bonded to the carbon atom or a nitrogen atom of the tetrazolyl group,
(av) a morpholinoalkyl group formed of a morpholino group and a C1-C3 alkylene group,
(aw) a 4-alkoxycarbonylcyclohexyl group wherein its alkoxyl group has one to six carbon atoms,
(ax) an alkoxycarbonyl group wherein its alkoxyl group has one to six carbon atoms,
(ay) an alkoxycarbonylalkyl group formed of a C1-C3 alkylene group and an alkoxycarbonyl group wherein its alkoxyl group has one to six carbon atoms,
(az) an 1-alkylindol-2-yl group wherein its alkyl group has one to six carbon atoms and the indole group may further have a substituent,
(ba) a pyrrolidon-1-yl group,
(bb) a 2-guanidinothiazolyl group,
(bc) a (2-guanidinothiazolyl)-alkyl group formed of a 2-guanidinothiazolyl group and a C1-C3 alkylene group,
(bd) a 1,4-dihydropyridyl group which may have a substituent,
(be) a 4-alkylpiperadinoalkyl group formed of a C1-C6 alkylene group and a 4-alkylpiperazino group having a C1-C6 alkyl group,
(bf) a 4-(morpholinosulfonyl)phenylalkyl group formed of a 4-(morpholinosulfonyl)phenyl group and a C1-C6 alkylene group,
(bg) a 4-(piperazinosulfonyl)phenylalkyl group formed of a 4-(piperazinosulfonyl)phenyl group and a C1-C6 alkylene group,
(bh) a 4-(piperazinosulfonyl)phenylalkyl group formed of a C1-C6 alkylene group and a 4-(4-alkylpiperazinosulfonyl)phenyl group having a C1-C6 alkyl group,
(bi) an alkoxycarbonylalkyl group formed of a C2-C7 alkoxycarbonyl group and a C1-C6 alkylene group,
(bj) a carboxylalkyl group formed of a carboxyl group and a C1-C6 alkylene group,
(bk) a [4-(4-dialkylaminopiperidino)phenyl]alkyl group formed of a C1-C6 alkylene group and a 4-(4-dialkylaminopiperidino)phenyl group wherein a 4-dialkylaminopiperidino group having, at the 4-position of the piperidine, a dialkylamino group containing two C1-C6 alkyl groups is bonded to the 4-position of the phenyl group,
(bl) a 4-(4-monoalkylaminopiperidino)phenylalkyl group formed of a C1-C6 alkylene group and a 4-(4-monoalkylaminopiperidino)phenyl group wherein a 4-monoalkylaminopiperidino group having, at the 4-position of the piperidine, a monoalkylamino group containing a C1-C6 alkyl group is bonded to the 4-position of the phenyl group,
(bm) a [4-(4-aminopiperidino)phenyl]alkyl group formed of a C1-C6 alkylene group and a 4-(4-aminopiperidino)phenyl group wherein a 4-aminopiperidino group is bonded to the 4-position of the phenyl group,
(bn) a (4-dialkylaminopiperidino)alkyl group formed of a C1-C6 alkylene group and a 4-dialkylaminopiperidino group wherein a dialkylamino group having two C1-C6 alkyl groups is bonded to the 4-position of the piperidine,
(bo) a (4-monoalkylaminopiperidino)alkyl group formed of a C1-C6 alkylene group and a 4-monoalkylaminopiperidino group wherein a monoalkylamino group having a C1-C6 alkyl group is bonded to the 4-position of the piperidine,
(bp) a (4-aminopiperidino)alkyl group formed of a 4-aminopiperidino group and a C1-C6 alkylene group, and
(bq) a hydrogen atom,
wherein when the substituents represented by (aa) through
(ap) have substituents, the substituents are one or more members selected from the group consisting of the following substituents:
1) a C1-C6 alkyl group,
2) a C1-C6 alkoxyl group,
3) a trifluoromethyl group and a 2,2,2-trifluoroethyl group,
4) a trifluoromethoxyl group and a 2,2,2-trifluoroethoxyl group,
5) a C1-C6 alkylthio group,
6) a C1-C6 alkylsulfinyl group,
7) a C1-C6 alkylsulfonyl group,
8) an alkanoyl group formed of a C1-C6 alkyl group and a carbonyl group,
9) a C2-C7 alkanoyloxy group,
10) a C2-C7 alkanoylamino group,
11) an amino group,
12) a monoalkylamino group having a C1-C6 alkyl group,
13) a dialkylamino group wherein each of the alkyl groups is a C1-C6 alkyl group,
14) a hydroxyl group,
15) a halogen atom,
16) a C2-C6 perfluoroalkyl group,
17) a cyano group,
18) a nitro group,
19) a carboxyl group,
20) an alkoxycarbonyl group formed of a C1-C6 alkoxyl group and a carbonyl group,
21) a tetrazolyl group,
22) a sulfamoyl group,
23) a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group,
24) a morpholinosulfonyl group,
25) a piperazinosulfonyl group,
26) a 4-alkylpiperazinosulfonyl group having a C1-C6 alkyl group,
27) a 4-(dialkylamino)piperadino group having a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other,
28) a 4-(monoalkylamino)piperidino group having a C1-C6 alkyl group, and
29) a 4-aminopiperidino group;
wherein the 6-membered ring portion of the bicyclic heterocyclic group (i) or the phenyl group (ii) may have one or more groups selected from among a C1-C6 alkyl group, a C1-C6 alkoxyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a trifluoromethoxyl group, a 2,2,2-trifluoroethoxyl group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C1-C6 alkylsulfonyl group, an alkanoyl group formed of a C1-C6 alkylene group and a carbonyl group, a C2-C7 alkanoyloxy group, a C2-C7 alkanoylamino group, an amino group, a monoalkylamino group having a C1-C6 alkyl groups, a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, a hydroxyl group, a halogen atom, a C2-C6 perfluoroalkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group formed of a C1-C6 alkoxyl group and a carbonyl group, a tetrazolyl group, a sulfamoyl group, a methylenedioxy group, an ethylenedioxy group, a morpholinosulfonyl group, a piperazinosulfonyl group, a 4-alkylpiperazinosulfonyl group having a C1-C6 alkyl group, a 4-dialkylaminopiperidino group having at the 4-position a dialkylamino group having two C1-C6 alkyl groups which may be identical to or different from each other, a 4-monoalkylaminopiperidino group having a C1-C6 alkyl group, or a 4-aminopiperidino group; and Z represents
(1) a C1-C3 alkylene group,
(2) a C2-C4 alkenylene group,
(3) a C1-C3 alkylene group having one hydroxyl group,
(4) a carbonyl moiety,
(5) a C1-C2 alkylene group containing one carbonyl moiety at one end or an intermediate position of the carbon chain, or
(6) an oxalyl group.
The present invention also provides an injection formulation containing the piperazine-cyclodextrin complex.
The present invention also provides a therapeutic agent for circulatory diseases, a therapeutic agent for brain diseases, and a brain protecting agent containing the piperazine-cyclodextrin complex as an active component.
The present invention further provides use of the piperazine-cyclodextrin complex as a pharmaceutical.
The present invention still further provides a method for treatment of circulatory diseases and brain diseases, characterized by administration of the piperazine-cyclodextrin complex.